The high (~45%) rate of unintended pregnancies in the US is largely due to incorrect or inconsistent use of contraceptives, indicating that available contraceptives are failing to meet women's needs. An ideal female contraceptive will: 1) be highly effective at preventing pregnancy, 2) not act as an abortifacient, 3) have no negative side effects, and 4) not depend on hormones. We propose that the potassium (K+) channel SLO3 is an ideal target for the development of a contraceptive that meets these criteria. This idea is founded on several unique aspects of SLO3 channels. First, SLO3 is absolutely required for sperm capacitation; mice lacking SLO3 are healthy but infertile because their sperm fail to undergo processes essential to their ability to fuse with an oocyte, hyperactivation (a vigorous type of motility essential to fertilization) and the acrosome reaction (release of the acrosome content). Second, these processes occur in the female genital tract, so a drug targeting SLO3 will be an effective, non-hormonal, non-abortifacient, female contraceptive. Finally, SLO3 channels are only expressed in sperm cells in humans and other mammals, so a contraceptive targeting this channel will affect no other cell in a woman's body. Our objective here is to develop inhibitors of SLO3 that will act as non-hormonal and reversible female contraceptives. To achieve our objective we will 1) employ high-throughput screening (HTS) to identify potent and specific small-molecule inhibitors of SLO3, 2) optimize SLO3 modulators via medicinal chemistry and 3) determine the effects of SLO3 inhibitors on sperm function. The research proposed here will identify lead molecules that can be developed into an innovative class of female contraceptives that act by targeting sperm capacitation. As a side benefit, this project may also produce activators of SLO3 that can be tested for their ability to promote premature sperm capacitation. Such compounds could then be developed as non-hormonal and reversible male contraceptives (SLO3 is not required for spermatogenesis). The information obtained from these studies will also contribute new knowledge to the field, specifically a deeper understanding of the role of ion channels in sperm physiology.